2-amino-5-halo-2&#39;-dialkylamino-and piperidino-benzophenones and preparation thereof



United States Patent "ice 3 261 867 2 AMINO HALO :2 -DIALKYLA1VHNO AND-PIPERIDINO-BENZOPHENONES AND PREPARA- TION THEREOF Rodney Ian Fryer,West Orange, and Leo Henryk Sternbach, Upper Montclair, N.J., assignorsto Holfmann- La Roche Inc., Nutley, N.J., a corporation of New Jersey NoDrawing. Filed Nov. 13, 1962, Ser. No. 237,347 4 Claims. (Cl. 260-570)Substituted ortho-aminobenzophenones have recently achieved importanceas intermediates useful in the preparation of therapeutically valuable5-phenyl-1,4-benzodiazepine 4-oxides and '5-phenyl-1,4benzodiazepin-2-ones; and methods :for obtaining said heterocycliccompounds from said ketones have been published, for example, the ketonecan be converted to its corresponding oxime which latter compound canthen be reacted with a 0:.- halo-acyl halide to produce thecorresponding ortho(ahalo-acylamino) benzophenone oXime, which then canbe dehydrated to the corresponding 2 halomethyl-4-phenyl quinazoline3-oxide, which latter compound, upon treatment with ammonia or a primaryamine, rearranges to a 2-amino-5-phenyl-1,4-benzodiazepine 4-oxide. Inanother method, 5-phenyl-l,4-benzodiazepin-2-ones can be prepared fromortho-aminobenzophenones by, for example, condensation of the ketonewith ethyl glycinate.

It has been found that S-phenyl-lA-benzodiazepin 4- oxides and5-phenyl-1,4-benzodiazepin-2-ones of particularly valuable therapeuticproperties are obtained when there is present an ortho or parasubstituent on the 5- phenyl ring. However, compounds bearing certainsubstituents on the 5-phenyl ring have, up to now, been obtainable onlyin a circuitous manner or, with respect to certain substituents, not atall.

The present invention provides a method for obtainingortho-aminoabenzophenous bearing in the 2'- or 4'- position, asubstituent selected from the group consisting of nitro, cyano, tertiaryamino, lower alkoxy and lower alkylthio. By the present invention, thesecompounds are obtained :from readily available 2-arnino-2 or4'-fluorobenzophenones. Certain of the compounds prepared by the methodsof this invention are novel and such compounds also form a part of thisinvention. By utilization of the 2 and 4' substituted benzophenonesobtained by this invention in known processes, therapeutically useful5-(2 or 4-substituted-phenyl)-l,4benzodiazepins can be obtained.

Thus, in one embodiment, the present invention comprises reacting acompound selected from the group consisting of ortho-fluorobenzophenonesand para-fluorobenzophenones with a compound selected from the groupconsisting of ammonia, di-lower alkylamine, lower alkyleneimine,aralykylamine, alkali metal lower alkoxide, alkali metal lowermercaptide and heavy metal lower mercaptide.

The present invention makes available ortho-aminobenzophenones bearingin the 2' or 4'-position a nitro, cyano, tertiary amino, lower alkoxy orlower alkylthio substituent .by two general approaches. The first ofthese comprises reacting an ortho-amino-2'- or4'-fluorobenzophenone'with a reactant which displaces the fluorine atomwith one of the aforesaid substituents. Thus, one embodiment of theinvention comprises the process for the preparation of compounds of theformula:

3,261,867 Patented July 19, 1966 wherein R is selected from the groupconsisting of hydrogen and lower alkyl; R is selected from the groupconsisting of hydrogen and tosyl; R is selected from the groupconsisting of hydrogen and middle halogen; one R is hydrogen and theother is selected from the group consisting of di-lower alkylamino,lower alkyleneimino, lower alkylthio and lower alkoxy which comprisesreacting a compound of the formula:

wherein one X is fluoro and the other is hydrogen, and R R and R havethe same meaning as above, with a compound selected from the groupconsisting of di-lower alkylamine, lower alkyleneimine, alkali metallower alkoxide, alkali metal lower mercapti-de and heavy metal lowermercaptide.

In a second approach of this invention an ortho-fluorobenzophenonecontaining the desired substituent on the non-fluorinated phenyl ring isreacted with a compound which displaces the fluorine and'supplies anamino group in lieu thereof, forexample, ammonia, a lower alkylamine oran aralkylamine, such as a phenyl-lower alkylamine as benzylamine. Whenan aralkylamine is utilized, the so-obtained compound can besubsequently dearalkylated. Thus, one embodiment of the inventioncomprises a process for the preparation of 2-amino-2' or 4'-R-benzophenone, wherein R is selected from the group consisting of cyanoand nitro, which comprises reacting 2 fluoro-2 or 4'-R-'benzophenonewith a compound selected from the group consisting of ammonia, loweralkylamine and aralkylamine.

As used in this disclosure, the term lower alkyl comprehends bothstraight and branched chain saturated hydrocarbon groups such as methyl,ethyl, propyl, isopropyl and the like. The term middle halogencomprehends the middle halogens, Viz. bromine and chlorine. The termlower alkylene comprehends saturated hydrocarbon groups such aspentylene and the like. The lower alkyl and lower alkylene groups indi-lower alkylamino, lower alkyleneimino, lower alkylthio and loweralkoxy are of the same character. vThus, di-lower alkylamino comprehendsgroups such as dimethylamino, lower alkyleneimino comprehends groupssuch as pipe'ridino, lower alkylthio comprehends groups such asmethylthio, and lower alkoxy comprehends groups such as methoxy. Alkalimetal comprehends the alkali metals such as sodium, lithium potassiumand the like. Heavy metal comprehends heavy metals which form stablesalts with the mercaptide radical such as mercury, lead and the like.

The fluorine displacement of the present invention can be conductedutilizing the fluorine displacing reactant as the solvent oralternatively in the presence of an organic solvent, such as ethanol,ethoxy-ethanol, benzene, toluene, dimethylformamide, dimethylsulfoxide,or the like. Thus, for example, if the fluorine displacing agent is anaralkylamine such as benzylamine, a lower alkyleneimine, such aspiperidine, or a di-lower alkylamine, the said reactant can also serveas the solvent medium. Alternatively, any of the aforesaid reactants canbe reacted with the above described fluorobenzophenones in the presenceof an organic solvent. When an alkali metal lower alkoxide or lowermercaptide is used as the fluorine displacement reactant, such can, forexample, be formed in situ. The alkali metal can be added to a loweralkanol such as methanol thereby forming a solution of sodium methoxiclein methanol, which is then used to treat the fluorobenzophenones, thusobtaining displacement of the fluorine substituent by a methoxy group.

When an alkali metal compound is used as a fluorine displacing reactant,the intermediate formed can be alkylated on the ortho-amino groupwithout isolation. Thus, in this aspect of the invention a 2-amino-2' or4'- fluorobenzophenone can be converted into a 2-lower alkylamino-2- or4-lower alkoxybenzophenone via tosylation of the starting materialaminofluorobenzop-henone so as to yield a 2-tosylamino-2' or4'-fiuorobenzophenone which upon treatment with an alkali metal loweralkoxide will simultaneously undergo displacement of the fluorine andreplacement thereof by a lower alkoxy group and formation of an alkalimetal salt of the 2-tosylarnino-2'- or 4'-lower alkoxy benzophenone thusformed. Treatment of this compound with a conventional alkylating agentwill then yield a Z-(N-lower alkyl-N-tosyl)-amino- 2' or 4'-loweralkoxy-benzophenone which can be detosylated by conventional means, forexample, by treatment with concentrated sulfuric acid. However, such adetosylation treatment will then result in a sulfonation of the loweralkoxysubstituted ring and the soformed sulfo group must be removed byconventional desulfonation methods, for example, by refluxing in 50%sulfuric acid/water.

Accordingly, a particular embodiment of the present invention comprisesa process for the preparation of 2- lower alkylamino-5-R-2'- or 4'-loweralkoxy benzophenone, which comprises reacting 2-tosylamino-5-R-2- or4'-fluorobenzophenone, wherein R is selected from the group consistingof hydrogen and middle halogen, with an alkali metal lower alkoxide andthen with an alkylating agent selected from the group consisting oflower alkyl-halide and di-lower alkylsulfate.

Temperature is not critical to the fluorine displacement reaction of thepresent invention. For example, it can be conducted at room temperature.However, it has been found that elevated temperatures increase the rateof the reaction. Similarly, pressure is not critical and the reactioncan be conducted at atmospheric pressure. However, pressures greaterthan atmospheric have been found to increase the rate of the reaction.Naturally, neither the temperature nor the pressure should be so high asto cause decomposition of the starting materials and/ or products.

Concentration of the reactants is not critical. Suitably, the fluorinedisplacing reactant is used in at least stoichiometric amounts.Advantageously, an excess of the fluorine displacing reactant is used.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in degrees centigrade.

Example 1 A solution of 2-amino-2'-fluorobenzophenone (1.4 mmoles) andsodium methoxide in methanol (20 ml. of a solution containing 4.44mmoles/ml.) in toluene (50 ml.) was refluxed for two hours. The solventswere removed under reduced pressure and the residue partitioned betweenwater (100 ml.) and methylene chloride (100 ml.). The organic layer wasseparated, washed with water (3 x 50 ml), saturated brine solution 2 x50 ml.), dried over anhydrous sodium sulfate, filtered and evaporated todryness, yielding 2-amino-2'-met=hoxybenzophenone as an oil which wascrystallized from ethanol yielding pale yellow needles melting at111112.

The above-mentioned starting material 2-amino-2- fluorobenzophenone isnot a part of this invention, but its preparation is set forth hereinbelow in order that this disclosure may be complete.

A mixture of 176 g. of ortho-fiuoro-benzoyl chloride and 64 g. ofpara-chloroaniline was stirred and heated to 180 C., at whichtemperature 87 g. of zinc chloride was introduced, the temperatureraised to 200-205 and maintained there for forty minutes. The goldencolored melt was quenched by the careful addition of 500 ml. of 3 Nhydrochloric acid and the resulting mixture refluxed for five minutes.The acid solution was decanted and the process repeated three times toremove all orthofluorobenzoic acid. The grey granular residue wasdissolved in 300 ml. of 75% (vol/vol.) sulphuric acid and refluxed forforty minutes to complete hydrolysis. The hot solution was poured over 1kg. of ice and diluted to two liters with water. The organic materialwas extracted with four 300 ml. portions of methylene chloride whichwere subsequently washed with two 500 ml. portions of 3 N hydrochloricacid to remove traces of para-chloroaniline, three 500 ml. portions of 5N sodium hydroxide solution to remove ortho-fluorobenzoic acid, andfinally two 200 ml. portions of saturated brine solution. The methylenechloride extract was dried over anhydrous sodium sulphate and thesolvent removed to give the crude aminobenzophenone. Recrystallizationfrom methanol gave 2 amino 5 chloro-2'-fluorobenzophenone yellow needls,(M.P. 94-95 50.0 g. of 2-amino-5-chloro-2-fluorobenzophenone in 300 cc.of tetrahydrofuran was hydrogenated at atmospheric pressure in thepresence of 10 g. of charcoal (Norite), 30.0 g. of potassium acetate and2.5 cc. of a 20% palladous chloride solution (20% by weight ofpalladium). After an initiation period varying from ten minutes to anhour, hydrogen uptake was rapid and stopped completely after theabsorption of the theoretical amount. Filtration of the catalyst over aHyflo pad and removal of the solvent left a yellow crystalline residue.The crude mixture of ketone and potassium acetate was partitionedbetween methylene chloride (300 cc.) and water (1 1.). The layers wereseparated and the Water layer washed with methylene chloride (3 x 50cc.) The organic layers were combined, washed with 3 N sodium hydroxidesolution (2 x 50 cc.), water (3 x cc.), saturated brine solution (3 x100 cc.), dried over anhydrous sodium sulfate and filtered. The solventwas removed and the product recrystallized from ethanol to give2-amino-2'-fluorobenzophenone as yellow prisms melting at 126-8.

Example 2 A solution of 2-tosylamino-2-fiuorobenzophenone (12 mmoles) intoluene (50 ml.) was refluxed with a methanolic solution of sodiummethoxide (25 ml. of a solution containing 4.44 moles of sodiummethoxide/ml.) for two hours. The solvents were evaporated under reducedpressure and the residue partitioned between water (100 ml.) andmethylene chloride (100 ml.). The organic layer was separated, washedwith water (3 x 50 ml.), saturated brine solution (2 x 50 ml), driedover anhydrous sodium sulfate, filtered and evaporated to dryness. Theresidual oil was crystallized from ethanol, yielding2-tosyla.mino-2'-methoxy-benzophenone as white prisms melting at134-135.

By the above procedure, the following compounds were prepared fromcorresponding 2-tosylamino-2-fluorobenzophenone:

2-tosylamino-5-bromo-2'-methoxy benzophenone, which formed white needlesmelting at 114-115.

2-tosylamino-5-chloro-4'-methoxy benzophenone, which formed whiteneedles melting at 128-130".

The above-mentioned 2-tosylamino-2-fluorobenzophe none startingmaterials are not a part of this invention, but their preparation is setforth hereinbelow in order that this disclosure may be complete.

A mixture of 2-amino-2'-fluorobenzophenone (3 g.) and p-toluenesulfonylchloride (3.2 g.) was dissolved in pyridine (15 cc.) and refluxed forninety minutes. A total of two-thirds of the pyridine was removed bydistillation and the residue poured into water (500 cc.). The mixturewas stirred until the product had solidified, and then filtered. Theprecipitate was dissolved in methylene chloride (50 cc.), and theresulting solution washed with 2 N hydrochloric acid (3 x 25 cc.), water(3 x 25 cc.), saturated brine solution (2 x 50 cc.), dried over anhy-.

drous sodium sulfate treated with Norite and filtered. Removal of thesolvent and crystallization of the residue from ethanol gave2-p-toluenesulfonamido-2'-fluorobenzophenone as white needles melting at1 29.5130.

The procedure used in the following preparation was essentially thatused for 2-amino-2-fluorobenzophenone described in Example 1 above.Reaction times and temperatures were varied as were hydrolysisconditions.

To a mixture of 580 g. of o-fluorobenzoyl chloride and 265 g. ofpbromoaniline at 180, 262 g. of zinc chloride was added with stirring.The temperature was raised to 195-205 and maintained there for twohours. The reaction mixture was quenched and washed with acid as in theprevious example, and the residue was hydrolyzed for twenty hours with 1liter of 60% (v./v.) sulphuric acid. The product,2-amino-5-bromo-2'-fluorobenzophenone, was extracted as before, yieldingyellow needles, M.P. '1-2.

A mixture of 50 g. of 2-amino-5-bromo-2'-fluorobenzophenone and 38.8 g.of p-toluenesulfonyl chloride was refluxed in 200 ml. of pyridine for 90minutes. The pyridine was then distilled off until the volume wasreduced to 100 ml., the residue poured into 250 ml. of water andstirred. The resulting precipitate was filtered oil and washed with 600ml. of hot Water followed by 300 ml. of petroleum solvent (B. 3040). Theresulting product was crystallized from methanol to give2-ptoluenesulfonamido 5 bromo-2'-fluorobenzophenone as white prismsmelting at 114-115 p-Fluorobenzoyl chloride (66 g.) was heated in a 2 1.three neck round bottom flask, fitted with a thermometer, condenser andstirrer, to 160 and p-chloroani-line (24 g.) was then added thereto. Thetemperature was raised to 200 and zinc chloride (33 g.) was introduced.The temperature was maintained at 200-210 for one hour and then thereaction was quenched by the careful addition of 250 cc. of 3 Nhydrochloric acid. The resulting mixture was refluxed for a few minutesand the acid portion decanted. The process of boiling with 250 cc.portions of 3 N hydrochloric acid was repeated three times. The residuewas then hydrolyzed by refluxing in 500 cc. of concentrated hydrochloricacid for 17 hours. The mixture was cooled and made alkaline with 10 Nsodium hydroxide, keeping the temperature below 30 by external cooling.The resulting yellow precipitate was filtered, dissolved in methylenechloride (300 cc.) and washed with 3 N hydrochloric acid (3 x 100 cc.).The organic layer was washed acid free with water (4 x 50 cc.), driedover anhydrous sodium sulfate, filtered and concentrated to an oil. Theresidue was dissolved in 2 l. of hexane, filtered, concentrated to 500cc. and allowed to crystallize. The crystals were filtered to giveyellow needles of 2-amino 5 chloro-4'-fluorobenzophenone melting at108-9.

A mixture of 2-amino-5-chloro-4'fluorobenzophenone (3.0 g.) andp-toluenesulfonyl chloride (2.8 g.) in pyridine cc.) was refluxed for 90minutes. Two-thirds of pyridine was removed by distillation and theresidue poured into 1 l. of water and stirred for one hour. Thecrystalline residue was filtered, dissolved in methylene chloride (150cc.) and the solution washed with 3 N hydrochloric acid (2 x 25 cc.),water (3 x 50 cc.), saturated brine solution (2 x 50 cc.), dried overanhydrous sodium sulfate and filtered. Methylene chloride was removedand the residue recrystallized from methanol to give2-p-toluenesulfonamido-5-chloro-4'-fluorobenzophe none as white prismsmelting at 126-8.

Example 3 A mixture of 2-tosylamino-5-chloro-2'-fluorobenzophenone(105.7 mmoles) and sodium methoxide (158.3 mmoles) in methanol (34. ml.)and toluene (100 ml.) was refluxed for 30 minutes. The reaction mixturewas concentrated to 40 ml. by distillation, cooled and dimet-hyl sulfateadded (158.5 mmoles). After an additional autoclave at 110 fortwenty-four hours.

ninety minutes.

i (200 m1.) and water (200 ml.).

reflux period of ninety minutes, 3 N sodium hydroxide solution ml.) wasadded and heating maintained for twenty minutes. The mixture was thencooled and the layers separated. The aqueous layer was Washed with ether(2 x 50 ml.), the organic layers combined and washed alkali free withsaturated brine (4 x 25 ml.). Removal of the solvent under reducedpressure gave an oil which soon crystallized. The product wasrecrystallined from ethanol, yielding 2 (N-methyl-N-tosylamino)-5-chloro-2-methoxybenzophenone, as white needles melting at 151.

' Using the above procedure, the following compound was prepared fromthe corresponding tosylaminobenzo- 'phen one 2 (Nmethyl-N-tosylamino)-5-bron1o2'-methoxybenzo phenone, which formed whiteneedles melting at 154- 155 The above-mentioned2-tosylamino-S-chloro-2'-fluorobenzophenone starting material is not apart of this invention, but its preparation is set forth hereinbelow inorder that this disclosure may be complete.

A mixture of 23.5 g. of Z-amino-S-chloro-Z'-fluorobenzophenone and 21.5g. of p-toluenesul-fonyl chloride was dissolved in 100 m1. of pyridineand refluxed for After distillation of 50 ml. of pyridine, the residuewas poured into 250 ml. of Water and stirred until the oil hadsolidified (thirty minutes). The precipitate was filtered and washedwith 600 ml. of hot water followed by 300 ml. of petrol (B.P. 30-40).The residue was recrystallized from methanol to give2-p-toluenesulfonamido-5-chloro-2'-fluorobenzop henone, yellow prismsM.P. 1l9120.

Example 4 A solution of 150 'g. of 2-amin o-5-chloro-2fluorobenzophenone in 500 ml. of benzene was refluxed for four hourswith a solution of 54 g. of sodium unethoxide in 230 ml. of methanol.The resulting solution was evaporated under reduced pressure to an oilwhich was dissolved in 5 00 ml. of ether, washed with water (3 X 200ml.)and dried over sodium sulfate. Filtration of the solution over 150 g. ofWoelm grade I neutral alumina and removal of the solvent gave an oilwhich was crystallized from an ether, hexane mixture yielding2-am-ino-5-chloro-2- methoxy'benzophenone as bright yellow prismsmelting at 81-83 Example 5 A standard solution of sodium methylmercaptan(96 ml. of a solution containing 200 rnmoles of NaSOH in 2-ethoxyethanol was refluxed for three hours with 25 g. ofZ-amino-5-chloro2'-fiuorobenzophenone. The solution was concentrated toapproximately 30 ml. by distillation and the residue partitioned betweenmethylene chloride The layers were separated, and the organic layerwashed with 3 \N hydrochloric acid (2 x 100 ml.), water (3 x 100 ml.),dried over anhydrous sodium sulfate, filtered and concentrated to anoil. A small portion .of the so-obta-ined 2-amino-5-chloro-2-methylthiobenzophenone was crystallized from hexane to give yellowplates, M.P. l0=0l00.5.

Example 6 A mixture of 20 g. of Zamrino-S-chloro-24fluorobenzophenone,71 ml. of an ethanolic solution of dimethylamine (400 mmoles) and 300ml. of ethanol was-heated in an (Initial pressure 100 psi. of N max.pressure 210 psi.) The cooled solution was concentrated to an oil underreduced pressure; dissolved in ether (300 ml.), washed with water (2 x50 m1.) and extracted into 9 N hydrochloric acid (4 x 100 ml.). The acidextracts were combined, washed with ether (2 X 100 ml.) made basic with10 N sodium hydroxide and the precipitated oil extracted intodiohloromethane (3 x 100 ml.). The combined organic layers were washedwith water (3 x 50 ml), dried over sodium sulfate and concentratedyielding 2-amino-5-chloro-2-dimethylaminobenzophenone as a bright yellowoil. An ether solution of the product was filtered over 50 g. ofalumina, concentrated and slowly crystallized from a hexane-ethermixture yielding yellow prisms melting at 856.

Example 7 A solution of 25 g. of 2-amino-5-chloro 2'-fluorobenzophenonein 100ml. of piperidine was refluxed for twentyfour hours, and thenevaporated under reduced pressure to an oil. The residue was thencontinuously extracted with boiling hexane until only a small amount ofdark insoluble material remained. The hexane extracts were combined,treated with decolorizing charcoal, filtered, concentrated and cooled,yielding Z-amino-5-chloro-2'-piper idinobenzophenone as bright yellowprisms. Recrystallization of a small portion of the product from hexaneyielded a purified sample melting at 1 1-0114.

Example 8 A mixture of 7.6 g. of 2-cyano-2'-fluorobenzophenone, and 6.7g. of benzylamine in 70 ml. of dry toluene was refluxed for two hoursand then concentrated, under reduced pressure, to a bright green oil.The oil was dissolved in 100 ml. of methylene chloride, washed withwater (3 x 75 ml.), dried over anhydrous sodium sulfate, filtered andconcentrated. Crystallization from ether gave 2-benzylamino2'-cyanobenzophenone, as yellow rods, melting at 142-143.5

A mixture of 6.0 g. of 2-benzylamino-T-cyanobenzophenone and 1.0 g. ofpalladium on charcoal and 1.4 ml. of concentrated hydrochloric acid in150 ml. of glacial acetic acid was reduced with hydrogen. The reactionwas stopped after forty minutes, when 1.15 mmoles of hydrogen had beenadsorbed, filtered, neutralized with ammonium hydroxide at 1015 andextracted with methylene chloride (3 x 100 ml.). The organic layers werecombined, washed with 100 ml. of 30% (w./w.) sodium carbonate solution,3 x 75 ml. of water, dried over anhydrous sodium sulfate, andevaporated. The residue was crystallized from an acetone, hexane mixtureto give Z-amino- 2'-cyanobenzophenone, as yellow plates melting at 132-3The above-mentioned 2-cyano-2'-fiuorobenzophenone is not a part of thisinvention, but its preparation is set forth hereinbelow in order thatthis disclosure may be complete.

A solution of 10.0 g. of 2-amino-2'-fiuorobenzophenone in ml. ofconcentrated sulfuric acid was added slowly to a cooled solution of 4.0g. of sodium nitrite in 40 ml. of concentrated sulfuric acid, keepingthe temperature below 10. The reaction mixture was stirred at roomtemperature for one hour, cooled in an ice bath and carefullyneutralized with a 30% (w./w.) solution of sodium carbonate. Theresulting solution of diazonium salt was then added over a period ofthirty minutes to a vigorously stirred, ice cold mixture of 1100 ml. ofbenzene and a solution of 6 g. of sodium cyanide, 4.5 g. of coppercyanide and 2.5 g. of sodium bicarbonate in 40 ml. of water. The mixturewas stirred at room temperature for one hour, then for five minutes at50, cooled and the layers separated. The aqueous layer was extractedwith 100 ml. of benzene. The organic layers were combined, washed with100 ml. of water, 50 ml. of saturated brine and evaporated to a brownoil. The oil was dissolved in ether and filtered through g. of Grade 1neutral alumina. The solution was concentrated and crystallized from anether, petroleum ether (BJP. -60) mixture to give 2-cyano2'-fluorobenzophenone as pale yellow rods, melting at 73-4".

Example 9 A solution of 12.0 g. of 2-nitro-2-fluorobenzophenone in 400ml. of ethanol saturated with ammonia was heated wherein R is hydrogen,lower alkyl or phenyl-lower alkyl; R is bromine or chlorine; and R isdi-lower alkylamino or piperidino.

2. 2-amino-5-chloro-2'-dimethylaminobenzophenone. 3. A process for thepreparation of a compound of the formula wherein R is hydrogen or loweralkyl, R is hydrogen or tosyl, R is bromine or chlorine and R isdi-lower alkylamino or piperidino, which comprises reacting a compoundof the formula Ih-N-Ra F wherein R R and R have the same meaning asabove with a compound selected from the group consisting of diloweralkylamine and piperidine.

4. A process which comprises reacting 2-amino-5-X-2- fluorobenzophenone,wherein X is bromine or chlorine, with dimethylamine.

References Cited by the Examiner UNITED STATES PATENTS 1,787,065 12/1930Calcott et al 260570 1,946,058 2/1934 Britton et a1 260570 2,231,0672/1941 Hammond et a1 260570 2,761,873 9/1956 Gregory et a1. 2605162,893,992 7/1959 Sternbach 260570 XR FOREIGN PATENTS 295,495 11/1916Germany.

OTHER REFERENCES Tanasescu et al., Bull. Soc. Chim. (5) 3, pages 1753-61 (1936).

Dziewonski et 211., Chemical Abstracts, vol. 30, pages 2971-2 (1936).

CHARLES B. PARKER, Primary Examiner.

D. R. MAHANAND, R. V. HINES,

Assistant Examiners.

1. A COMPOUND OF THE FORMULA